Topical antifungal compositions

ABSTRACT

Aqueous, topical compositions contain an allylamine or an azole as an antifungal agent together with a lactate ester, an organic acid (pKa 3.8-5), ethanol, water, and a cationic galactomannan gum.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. patent applicationSer. No. 15/760,390, filed on Mar. 15, 2018, which application is a 371National Stage entry of PCT/US2016/055978, filed on Oct. 7, 2016, andclaims benefit of U.S. Provisional Application No. 62/238,464, filed onOct. 7, 2015, all incorporated herein by reference in their entireties.

FIELD OF INVENTION

This invention relates to topical antifungal compositions. Moreparticularly, this invention relates to topical antifungal compositionshaving enhanced antifungal activity.

BACKGROUND OF THE INVENTION

Infections of skin, nails, hair, or mucous membranes by fungi arecommon.

Onychomycosis, in particular, is a frequent fungal infection of nails,involving up to about 15% of adult individuals between the ages of about40 to about 60 years. Delivery of antifungal agents through the nail andinto the nail beds as well as the surrounding skin has been difficult todate, and minimally effective.

SUMMARY OF INVENTION

A topical antifungal composition is provided. The antifungal agent is anallylamine or an azole. Also present in the topical composition arelactate esters of a C₂ to C₁₆ saturated aliphatic alcohol, an organicacid having a pKa value in the range of about 3.8 to about 5, ethanol,water, and a cationic galactomannan gum, preferably a cationicpolygalactomannan gum ether salt.

A preferred allylamine antifungal agent is terbinafine hydrochloride. Apreferred azole antifungal agent is efinaconazole. A preferred lactateester is lauryl lactate. A preferred organic acid is acetic acid orlactic acid.

BRIEF DESCRIPTION OF DRAWINGS

In the drawings,

FIG. 1 shows shed snake skin permeation profiles of an aqueousterbinafine gel containing terbinafine hydrochloride, lauryl lactate,lactic acid, ethyl alcohol, water and hydroxypropyl guar hydroxypropyltrimonium chloride, as well as that of a commercially availableterbinafine hydrochloride cream (1%) (Lamisil AT® Antifungal Cream);

FIG. 2 shows the permeation profiles through a male cadaver nail of thesame compositions as in FIG. 1;

FIG. 3 shows the permeation profiles through the same male cadaver nailof the same compositions as in FIG. 1 measured one week after thepermeation profiles shown in FIG. 2 were obtained;

FIG. 4 shows the permeation profiles through the same male cadaver nailof the same compositions as in FIG. 1 measured one week after thepermeation profiles shown in FIG. 3 were obtained;

FIG. 5 shows terbinafine hydrochloride retention profile after twoconsecutive male cadaver nail permeation studies performed one weekapart;

FIG. 6 shows terbinafine hydrochloride shed snake skin permeationprofiles in topical compositions containing monoprotic and polyproticorganic acids having different pKa values;

FIG. 7 shows shed snake skin permeation profiles of an aqueousamorolfine gel containing amorolfine hydrochloride, lauryl lactate,lactic acid, ethyl alcohol, water, and hydroxypropyl guarhydroxypropyltrimonium chloride as well as that of a commerciallyavailable amorolfine hydrochloride preparation, Loceryl® (5%) cream;

FIG. 8 shows shed snake skin permeation profiles of an aqueousterbinafine gel with various lactic, levulinic and acetic acid levels;

FIG. 9 shows shed snake skin permeation profiles of an aqueousterbinafine gel with cationic and nonionic guar gum thickeners; and

FIG. 10 shows cadaver skin permeation profiles for present antifungalefinaconazole compositions as well as that of a commercially availableefinaconazole containing cream (10%) (Jublia® cream).

DESCRIPTION OF PREFERRED EMBODIMENTS

The present aqueous topical compositions have the consistency of a gel,i.e., a substantially homogeneous semi-solid preparation having a liquidphase within a three dimensional polymeric matrix.

Suitable allylamine antifungal agents for the present compositions areterbinafine, naftifine, the allylamine-like compounds butenafine,amorolfine, as well as pharmaceutically acceptable salts of theforegoing. A preferred allylamine antifungal agent is terbinafinehydrochloride.

Allylamines inhibit ergosterol synthesis by fungi by the inhibition ofsqualene epoxidase, an enzyme involved in the fungal cell membranesynthesis pathway that prevents conversion of squalene to lanosterol,thereby inducing fungal cell lysis. In the present topical compositions,the allylamine is present in an amount in the range of about 0.5 toabout 3 percent by weight, preferably about 1.2 percent by weight, basedon the total weight of the composition.

Suitable azole antifungal agents for the present compositions are theimidazoles, the triazoles, and the thiazoles. Azole antifungal agentshave similar activity against fungi as the allylamines, i.e., inhibitionof the need to convert lanosterol to ergosterol. In the present topicalcompositions, the azole is present in an amount in the range of about0.1 to about 5 percent by weight, preferably about 2 percent by weight,based on the total weight of the composition.

Illustrative imidazoles are ketoconazole, miconazole, isoconazole,clotrimazole, and the like.

Illustrative triazoles are efinaconazole, fluconazole, intraconazole,terconazole, and the like.

Illustrative thiazoles are abafungin, ethaboxam, thiabendazole,thiafluzamide, and the like.

Suitable lactate esters are the reaction products of lactic acid with aC₂ to C₁₆ saturated aliphatic alcohol. Illustrative such lactate estersare ethyl lactate, propyl lactate, n-butyl lactate, isoamyl lactate,2-ethylhexyl lactate, lauryl lactate, cetyl lactate, and the like.

Lauryl lactate (C₁₅H₃₀O₃), the ester of lauryl alcohol and lactic acid,is a preferred lactate ester and is represented by the formula:

The lactate ester is present in the topical antifungal compositions inan amount in the range of about 1 to about 5 percent by weight,preferably about 3.5 percent by weight, based on the total weight of thecomposition.

Suitable organic acids for incorporation into the topical antifungalcompositions can be monoprotic or polyprotic and have a pKa value in therange of about 3.8 to about 5. Illustrative monoprotic organic acids areglycolic acid (pKa 3.8), lactic acid (pKa 3.9), hydroxymethylbutyricacid (pKa 4.55), levulinic acid (pKa 4.6), acetic acid (pKa 4.8),caproic (hexanoic) acid (pKa 4.88), and the like. Illustrative diproticacids are methyl succinic acid (pKa 4.13 and 5.64), succinic acid (pKa4.21 and 5.64), glutaric acid (pKa 4.32 and 5.42) and the like.Monoprotic organic acids such as acetic acid and lactic acid arepreferred.

The organic acid content of the present compositions is in the range ofabout 0.5 to about 5, preferably about 1 to about 4, percent by weight,based on the total weight of the composition.

The amount of ethanol present in the composition can be in the range ofabout 35 to about 55 percent, preferably about 40 to about 50 percent,by weight of the composition. The preferred organic acid-to-ethanolratio is in the range of about 0.04 to about 0.09

The amount of water, preferably deionized water, can be present in thecomposition in the range of about 35 to about 55 percent, preferablyabout 40 to about 50 percent, by weight of the composition. Thepreferred water-to-ethanol weight ratio is in the range of about 1 to1.1.

Another constituent of the topical antifungal compositions is agalactomannan gum derivatized with a cationic substituent. Nonionicsubstituents can be present as well.

The term “degree of substitution” or “DS” is used herein to indicate theaverage number of cationic-substituted hydroxyl groups relative to thetotal number of available hydroxyl groups per monomeric sugar unit inthe guar polymer or gum. The monomeric sugar units of guar gum have onthe average three (3) hydroxyl groups available for functionalization.Thus the value of DS is necessarily in the range of 0 to 3. ADS value of0.10 corresponds to ten (10) cationic groups per every 100 sugar units.

For cationic galactomannan gums such as cationic guar gum the degree ofsubstitution or DS preferably has a value in the range of about 0.07 toabout 0.2.

The term “molar substitution” or “MS” is used herein to indicate thenumber of nonionic-substituted hydroxyl groups relative to the totalnumber of available hydroxyl groups per monomeric sugar unit in the guarpolymer or gum. Typical nonionic substituents are the hydroxyalkylgroups such as the hydroxyethyl and hydroxypropyl groups. For cationicgalactomannan gums such as cationic guar gum the molar substitution orMS preferably has a value in the range of about 0.4 to 0.8.

Illustrative are guar hydroxypropyl trimonium chloride, hydroxypropylguar trimonium chloride, and the like. Preferred are salts of a cationicpolygalactomannan gum ether. This particular constituent has been foundto provide an unexpected but desirable enhancement in the skinpermeation of the active antifungal agent in the presence of the lactateester and the monoprotic organic acid. Particularly preferred ishydroxypropyl guar hydroxypropyl trimonium chloride. Other quaternaryammonium derivatives of gums can be used as well for this purpose.

The cationic galactomannan gum can be present in an amount in the rangeof about 1 to about 3 percent by weight (dry basis), preferably about 2to about 2.5 percent by weight (dry basis), based on the total weight ofthe composition.

The topical antifungal compositions can be prepared in the followingmanner:

The cationic galactomannan gum, such as hydroxypropyl guar hydroxypropyltrimonium chloride, is thoroughly dispersed in water. In a separatevessel the antifungal agent is combined with the lactate ester and theother remaining ingredients, and the resulting mixture is dissolved inethanol. After the added organic acid has been dissolved, an aliquot ofwater is added with thorough mixing.

The obtained water-ethanol solution is then combined with the cationicgalactomannan gum dispersion with vigorous agitation for a time periodof at least about two hours until a substantially homogeneous gel isachieved. Thereafter any entrained air bubbles are removed. Preferably,the obtained gel is left standing before packaging for a time periodsufficient for any entrained air bubbles to disperse.

An illustrative topical antifungal composition embodying the inventionis set forth in Table I below.

TABLE 1 Topical Antifungal Composition (Composition A) IngredientAmount, wt.-% Terbinafine HCl 1.2 Lauryl lactate¹ 3.5 Lactic acid 2.4Water, deionized 47.1 Ethyl alcohol USP (200 proof) 43.4 Hydroxypropylguar hydroxypropyl 2.4 trimonium chloride² Water/Ethanol 1.085 Lacticacid/Ethanol 0.055 TOTAL 100 ¹Schercemol LL ester ²Jaguar C162; CAS No.71329-50-5; DS 0.10; MS 0.6; contains 11.5% w/w water (Solvay USA Inc.,Cranbury, NJ 08512-7500)

A skin permeation study was performed with the composition shown inTable 1 using shed snake skin in a Franz cell (3.65 ml volume, 0.55 cm²surface area) with heating/stirring blocks and at a temperature of 35°C. Receptor compartment contained saline with sodium azide (pH 5.5).Three or four replicates (25 μl and a 25 mg control) were prepared.Sampling volume was 300 μl. Fresh buffer was replaced after each sampleremoval. Sampling was carried out at 4, 6 and 24 hours. The obtainedsamples were assayed using high performance liquid chromatography(HPLC). The control was a terbinafine containing cream (1%) commerciallyavailable under the designation Lamisil AT® antifungal cream.

The obtained permeation profile for the composition in Table 1, above,is presented in FIG. 1 and in Table 2, below.

TABLE 2 Permeation Data Cumulative Amount in Receptor, μg/cm² Time, Hrs.Composition A ±SD Control ±SD 4 2.05 0.26 1.48 0.06 6 2.32 0.81 1.790.15 24 14.30 7.07 1.91 0.15

The foregoing data show enhanced permeation of terbinafine hydrochlorideas compared to the commercially available composition which containsapproximately the same amount of terbinafine.

Permeation of Composition A through cadaver nails was studied in Franzcells, as described hereinabove, using a set of the cadaver nails from a52-year old male as the Franz cell membrane. Cadaver nails were obtainedfrom Science Care, Phoenix, Ariz.

The nail thickness was measured to be 0.65 to 1 millimeter.

Phosphate buffered saline (PBS, pH 5.5) was used as the receptor phaseduring each study.

Composition A was applied daily to each nail during the course of eachstudy.

A one-week time period between successive studies was maintained. Duringthis one-week time period the Franz cells were kept at 32° C. withstirring but no application of Composition A or sampling was takingplace.

At the beginning of the next study, the receptor phase was removed, thereceptor was rinsed with PBS at pH 5.5, and fresh PBS at pH 5.5 wasintroduced into the receptor compartment.

The control was a terbinafine-containing cream (1%) commerciallyavailable under the designation Lamisil AT® antifungal cream.

The results of three consecutive studies using the same cadaver nail setare presented in FIGS. 2, 3 and 4 and in Tables 3, 4 and 5 below.

TABLE 3 Nail Permeation Data (Study 1) Cumulative Amount in Receptor,μg/cm² Time, Hrs. Composition A ±SD Control ±SD 48 0.42 0.04 0.08 0 961.27 0.96 0.07 0 144 2.79 0.44 0.06 0

TABLE 4 Nail Permeation Data (Study 2) Cumulative Amount in Receptor,μg/cm² Time, Hrs. Composition A ±SD Control ±SD 48 4.88 2.11 0.47 0.6796 16.17 3.54 0.39 0.03 144 27.94 10.87 0.41 0.47 216 43.14 6.84 0.830.69 264 56.19 8.84 1.07 1.19

TABLE 5 Nail Permeation Data (Study 3) Cumulative Amount in Receptor,μg/cm² Time, Hrs. Composition A ±SD Control ±SD 48 22.04 13.41 0.15 0.07288 51.14 12.04 0.25 0.15 336 68.52 21.79 0.20 0.16 672 110.79 62.600.25 0.01

The foregoing nail permeation data show that the composition embodyingthe present invention provides significantly enhanced terbinafinepermeation through the human nail as compared to a commerciallyavailable topical terbinafine cream. In addition the foregoing data showthat terbinafine from the present topical compositions accumulates or isretained in the nail.

After the completion of the aforedescribed nail permeation studies, thenails were removed from the Franz cells, wiped dry with lint free papertissues (Kim-Wipes™) further cleaned twice with Qtips® cotton swabssoaked in absolute ethanol, and then dried at room temperature.

The dried nails then were cut into pieces (2 mm×2 mm) with stainlesssteel scissors, transferred into capped vials and extracted with ethanol(about 2 ml/vial) overnight at 37° C. with agitation. The obtainedextracts were centrifuged and the obtained supernatant liquid analyzedby HPLC.

The obtained terbinafine retention profile is shown in FIG. 5 andpresented in Table 6, below.

TABLE 6 Nail Retention Profile Average Amount Composition Retained,μg/cm² ±SD Composition A 29.51 11.23 Control 2.88 2.5

The above data show that a considerably larger amount of Composition Awas retained in the nail as compared to the control, Lamisil AT®antifungal cream.

The permeability profiles of terbinafine topical antifungal compositionscontaining various organic acids with different dissociation constants(pKa values) were investigated. The compositions are set forth in Table7, below. The permeation profiles of these compositions were determinedin Franz cells using shed snake skin membranes.

TABLE 7 Terbinafine Antifungal Compositions Composition LamisilIngredient/wt.-% A B C D E F G H I J² AT ® Terbinafine HCl 1.2 1.2 1.21.2 1.2 1.2 1.2 1.2 1.2 1.2 1 Lauryl lactate 3.5 3.5 3.5 3.5 3.5 3.5 3.53.5 3.5 3.5 Water, deionized 47.1 47.1 47.1 47.1 47.1 47.1 47.1 47.147.1 45.8 Ethyl alcohol USP (200 Proof) 43.4 43.4 43.4 43.4 43.4 43.443.4 43.4 44.6 43.5 Jaguar C162¹ 2.4 2.4 2.4 2.4 2.4 2.4 2.4 2.4 1.2 3.6Lactic acid (pKa 3.9) 2.4 2.4 2.4 Levulinic acid (pKa 4.6) 2.4Hydroxymethylbutyric acid 2.4 (pKa 4.55) Citric acid (pKa 3.09; 4.75;2.4 5.41) Acetic acid (pKa 4.8) 2.4 Maleic acid (pKa 1.93; 6.58) 2.4Malic acid (pKa 3.40; 5.2) 2.4 Caproic acid (pKa 4.88) 2.4 TOTAL 100 100100 100 100 100 100 100 100 100 ¹Hydroxypropyl guar hydroxypropyltrimonium chloride; CAS No. 71329-50-5; contains 11.5% w/w water²Composition J exhibited unacceptably high viscosity

The obtained permeation profiles are shown in FIG. 6, and are presentedin Table 8, below.

TABLE 8 Permeation Profiles of Compositions A-I Cumulative Amount(μg/cm²) per Composition Time, Lamisil Hrs. A ± SD B ± SD C ± SD D ± SDE ± SD F ± SD G ± SD H ± SD I ± SD AT ® 2 0.00 ± 0.00  0.00 ± 0.00  0.00± 0.00 0.00 ± 0.00  0.00 ± 0.00 0.00 ± 0.00 0.00 ± 0.00  0.00 ± 0.000.00 ± 0.00 0.00 4 0.00 ± 0.00  0.00 ± 0.00  0.00 ± 0.00 0.00 ± 0.00 0.00 ± 0.00 0.00 ± 0.00 0.00 ± 0.00  0.00 ± 0.00 0.00 ± 0.00 0.00 60.83 ± 0.38  1.98 ± 0.81  1.41 ± 0.46 0.53 ± 0.26  2.88 ± 0.52 0.93 ±1.04 0.35 ± 0.20  2.11 ± 0.17 1.92 ± 1.98 1.01 22 7.36 ± 2.94 21.43 ±1.51 17.38 ± 6.83 1.58 ± 1.14 22.69 ± 1.98 0.85 ± 0.22 2.77 ± 1.33 19.07± 5.13 7.60 ± 6.93 1.15

The above data show that all but Composition F exhibited enhancedpermeation as compared to commercial product Lamisil AT® antifungalcream, and that Compositions A, B, C, E, H and I, containing amonoprotic organic acid with a pKa value in the range of about 3.8 toabout 5 exhibited substantially enhanced permeation.

Stability of Composition A samples was evaluated by storage at 25° C.and 40° C. for extended time periods in phenolic capped glass vials.Thereafter aliquots of the stored samples were analyzed by highperformance liquid chromatography (HPLC). The observed results are shownin Table 9, below.

TABLE 9 Stability of Terbinafine Hydrohchloride Containing Composition ATerbinafine Storage Amount HCl, Temperature, Time, Recovered, wt.-% ° C.months wt.-% ±SD 1.2 25 2 109.19 2.24 1.2 25 4 108.04 3.30 1.2 25 7107.97 0.66 1.2 40 1 112.6 1.39 1.2 40 3 110.33 1.16 1.2 40 6 110.070.38

HPLC chromatograms of aliquots taken from the stored samples did notreveal any peaks due to decomposition. Similar permeation profiles wereobserved for samples stored for four months at 25° C. and at 40° C.

The slightly higher observed values for amounts recovered are believedto be due to some loss of ethyl alcohol due to the containers used tostore the samples.

Further illustrative topical antifungal compositions embodying theinvention are set forth in Table 10, below.

TABLE 10 Topical Antifungal Compositions (Compositions K and L) Amountwt.-% Ingredient K L Amorolfine HCl 1.2 2.4 Lauryl lactate¹ 3.5 3.5Lactic acid 2.4 2.4 Water, deionized 47.1 45.8 Ethyl alcohol USP,absolute 43.4 43.5 Hydroxypropyl guar hydroxypropyl 2.4 2.4 trimoniumchloride² Water/Ethanol 1.085 1.053 Lactic acid/Ethanol 0.056 0.55 TOTAL100 100 ¹Schercemol LL ester ²Jaguar C162; CAS No. 71329-50-5; DS 0.10;MS 0.6; contains 11.5% w/w water

A skin permeation study was performed using the compositions shown inTable 10, above. Shed snake skin was used in a Franz cell (3.65 mlvolume, 0.55 cm² surface area) with heating/stirring blocks and at atemperature of 35° C. Receptor compartment contained saline with sodiumazide (pH 5.5). Three or four replicates (25 μland a 25 mg control) wereprepared. Sampling volume was 300 μL. Fresh buffer was replaced aftereach sample removal. Sampling was carried out at 2, 4, 6 and 24 hours.The obtained samples were assayed using high performance liquidchromatography (HPLC). The control was a commercially available,amorolfine containing cream (5%), Loceryl® cream, Galderma Laboratorium,Germany, having the following composition:

-   -   amorolfine HCl (5%)    -   ammonio methacrylate polymer    -   triacetin    -   butyl acetate    -   ethyl acetate    -   ethanol (61%).

The obtained permeation profiles for the compositions in Table 10 arepresented in FIG. 7 and Table 11, below.

TABLE 11 Permeation Data Time, Cumulative Amount in Receptor, μg/cm²Hrs. Composition K ±SD Composition L ±SD Loceryl ® ±SD 2 0 0 0 0 0 0 4 00 0 0 0 0 6 8.46 2.17 13.05 2.85 1.49 0.64 24 19.49 2.94 29.66 9.63 1.870.96

The foregoing data show enhanced permeation of amorolfine hydrochlorideas compared to commercially available preparations containing the sameactive ingredient albeit at a relatively higher concentration.

The permeation profiles of terbinafine antifungal compositions throughshed snake skin at varying concentrations of lactic acid, levulinic acidand acetic acid were evaluated. The evaluated compositions are shown inTable 12, below. The observed permeation profiles are presented in FIG.8 and Table 13, below.

TABLE 12 Terbinafine Antifungal Compositions Composition LamisilIngredient/wt.-% A M N B O P E Q R AT ® Terbinafine HCl 1.2 1.2 1.2 1.21.2 1.2 1.2 1.2 1.2 1 Lauryl lactate 3.5 3.5 3.5 3.5 3.5 3.5 3.5 3.5 3.5Water, deionized 47.1 47.1 45.8 47.1 47.1 45.8 47.1 47.1 45.8 Ethylalcohol USP 43.4 44.6 43.5 43.4 44.6 43.5 43.4 44.6 43.5 (200 Proof)Jaguar C162¹ 2.4 2.4 2.4 2.4 2.4 2.4 2.4 2.4 2.4 Lactic acid (pKa 3.9)2.4 1.2 3.6 Levulinic acid (pKa 4.6) 2.4 1.2 3.6 Acetic acid (pKa 4.8)2.4 1.2 3.6 TOTAL 100 100 100 100 100 100 100 100 100 ¹Hydroxypropylguar hydroxypropyl trimonium chloride; CAS No. 71329-50-5; DS 0.10; MS0.6; contains 11.5% w/w water

TABLE 13 Permeation Profiles of Compositions in Table 12 Time,Cumulative Amount (μg/cm²) per Composition Hrs. A ± SD B ± SD E ± SD M ±SD N ± SD O ± SD 2 0.00 ± 0.00 0.00 ± 0.00  0.00 ± 0.00 0.00 ± 0.00 0.00± 0.00 0.00 ± 0.00 4 6.06 ± 1.68 12.08 ± 8.33  25.02 ± 2.86 5.50 ± 1.995.00 ± 1.21 5.35 ± 0.31 6 9.82 ± 0.65 18.78 ± 2.44  45.67 ± 2.82 7.53 ±1.99 11.87 ± 4.40  7.84 ± 2.20 24 37.4 ± 7.67 55.70 ± 12.55 85.04 ± 4.2431.61 ± 4.45  70.34 ± 29.42 27.43 ± 1.86  Time, Cumulative Amount(μg/cm²) per Composition Hrs. P ± SD Q ± SD R ± SD Lamisil AT ® 2 0.00 ±0.00  0.00 ± 0.00 0.00 ± 0.00 0.00 ± 0.00 4 6.51 ± 3.48 13.65 ± 5.5734.91 ± 11.06 1.77 ± 1.47 6 20.06 ± 8.19  19.14 ± 0.29 58.08 ± 16.911.66 ± 1.12 24 84.06 ± 17.36 33.64 ± 7.52 110.14 ± 38.24  2.23 ± 1.59

The above data show that relatively higher acid content enhancedpermeation, and that acetic acid containing compositions providedhighest permeation.

The permeation profiles of terbinafine antifungal compositions throughshed snake skin and utilizing various guar gums were evaluated as well.The evaluated compositions are shown in Table 14, below. The observedpermeation profiles are presented in FIG. 9 and Table 15, below.

TABLE 14 Terbinafine Antifungal Compositions CompositionIngredient/wt.-% A S T Lamisil AT ® Terbinafine HCl 1.2 1.2 1.2 1 Lauryllactate 3.5 3.5 3.5 Lactic acid 2.4 2.4 2.4 Water, deionized 47.1 47.147.1 Ethyl alcohol USP (200 proof) 43.4 43.4 43.4 Jaguar C162¹ 2.4Jaguar HP 105² 2.4 Jaguar HP 120³ 2.4 TOTAL 100 100 100 ¹Hydroxypropylguar hydroxypropyl trimonium chloride; CAS No. 71329-50-5; DS 0.10; MS0.6; contains 11.5% w/w water ²Nonionic guar gum, 2-hydroxypropyl ether;CAS No. 39421; contains 6.4% w/w water; 0.6 MS ³Nonionic guar gum,2-hydroxypropyl ether; CAS No. 39421-75-5; contains 7.5% w/w water; 1.2MS

TABLE 15 Permeation Profiles of Compositions in Table 14 CumulativeAmount (μg/cm²) per Composition Time, Hrs. A ± SD S ± SD T ± SD LamisilAT  ® ± SD 2 0.00 ± 0.00 0.00 ± 0.00 0.00 ± 0.00 0.00 ± 0.00 4 5.99 ±2.83 2.88 ± 0.68 1.85 ± 0.45 2.23 ± 0.68 6 22.43 ± 6.82  6.10 ± 1.446.40 ± 1.83 2.39 ± 0.78

The above data show that a cationic guar gum provides a betterpermeation profile as compared to a nonionic guar gum.

The permeation behavior through shed snake skin of Composition A storedfor a time period of six months at 25° C. and 40° C. was evaluated aswell. The observed results are shown in Table 16, below.

TABLE 16 Permeation Profile of Composition A After Storage CumulativeAmount (μg/cm²) per Composition Time, Hrs. A ± SD @ 25° C. A ± SD @ 40°C. Lamisil AT ® ± SD 2 12.08 ± 2.39 21.76 ± 8.27 1.59 ± 0.17 6  31.07 ±12.77  60.92 ± 19.75 1.44 ± 0.33 24 161.57 ± 52.44 204.40 ± 25.06 2.98 ±0.88

Illustrative terbinafine antifungal compositions containing diproticorganic acids are shown in Table 17, below, and their permeation throughshed shake skin is shown in Table 18, below.

TABLE 17 Terbinafine Antifungal Compositions With Diprotic Organic AcidsComposition Ingredient/wt.-% A U V Lamisil AT ® Terbinafine HCl 1.2 1.21.2 1 Lauryl lactate 3.5 3.5 3.5 Water, deionized 47.1 47.1 47.1 Ethylalcohol USP (200 proof) 43.4 43.4 43.4 Jaguar C162¹ 2.4 2.4 2.4 Lacticacid (pKa 3.9) 2.4 Succinic acid (pKa 4.21; 5.64) 2.4 Glutaric acid (pKa4.32; 5.42) 2.4 TOTAL 100 100 100 ¹Hydroxypropyl guar hydroxypropyltrimonium chloride; CAS No. 71329-50-5; DS 0.10; MS 0.6; contains 11.5%w/w water

TABLE 18 Permeation Profiles of Compositions A, U & V Cumulative Amount(μg/cm²) per Composition Time, Lamisil Hrs. A ± SD U ± SD V ± SD AT ® ±SD 4 12.08 ± 2.39  9.98 ± 2.23  9.49 ± 1.30 1.59 ± 0.17 6  31.07 ± 12.7726.36 ± 7.96 29.15 ± 8.28 1.44 ± 0.33 24 161.57 ± 52.44 142.75 ± 38.24163.22 ± 46.03 2.98 ± 0.88

Stability of Composition E and Composition R, both containing aceticacid, was evaluated after storage at 25° C. and 40° C. for a time periodof one month and three months in phenolic capped glass vials. Aliquotsof stored samples were analyzed by high performance liquidchromatography. The observed results are shown in Tables 19 and 20,below.

TABLE 19 Stability of Terbinafine Hydrochloride Containing Composition ETerbinafine Storage Amount HCl, Temperature, Time, Recovered, wt.-% ° C.months wt.-% ±SD 1.2 25 0 104.53 1.53 1.2 25 1 105.30 1.06 1.2 25 3102.15 2.33 1.2 40 0 104.53 1.53 1.2 40 1 105.02 0.95 1.2 40 3 103.822.11

TABLE 20 Stability of Terbinafine Hydrochloride Containing Composition RTerbinafine Storage Amount HCl, Temperature, Time, Recovered, wt.-% ° C.months wt.-% ±SD 1.2 25 0 105.39 0.81 1.2 25 1 105.55 0.49 1.2 25 3104.54 1.04 1.2 40 0 105.39 0.81 1.2 40 1 104.68 0.99 1.2 40 3 107.172.42

Data in the above Tables shows that the terbinafine hydrochloridecompositions were stable after storage for three months at 25° C. and40° C. in phenolic capped glass vials. The somewhat higher assays ofrecovered terbinafine hydrochloride are believed to be due to loss ofethanol by evaporation.

A preferred allylamine antifungal composition is a topical gel whichincludes terbinafine hydrochloride, lauryl lactate, water, ethanol,hydroxypropyl guar hydroxypropyl trimonium chloride and acetic acid.

A preferred water-to-ethanol weight ratio is in the range of about 1 toabout 1.1.

A preferred acetic acid-to-ethanol weight ratio is in the range of about0.04 to about 0.09.

A preferred amount of acetic acid for terbinafine hydrochloride topicalgel compositions is in the range of about 2 to about 4 percent byweight, based on the total weight of the topical gel composition.

In a preferred topical gel composition terbinafine hydrochloride ispresent in an amount in the range of 0.5 to about 3 percent by weight,lauryl lactate is present in an amount in the range of about 1 to about5 percent by weight, water, more preferably deionized water, is presentin an amount in the range of about 35 to about 55 percent by weight,more preferably about 40 to about 50 percent by weight, ethanol ispresent in an amount in the range of about 35 to about 55 percent byweight, more preferably about 40 to about 50 percent by weight, and thehydroxypropyl guar hydroxypropyl trimonium chloride is present in anamount in the range of about 1.5 to about 3 percent by weight, morepreferably about 2 to about 2.5 percent by weight. The aforesaidpercentages by weight are based on the total weight of the topical gelcomposition.

The effect of water-ethanol weight ratio on terbinafine hydrochloridecontaining topical compositions is illustrated in Tables 21 and 22,below.

TABLE 21 Terbinafine HCl Compositions With Different Water/EthanolWeight Ratios Composition Ingredient, wt.-% R AA AB AC AD AE AF AG AHTerbinafine HCl 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2 Lauryl lactate¹ 3.53.5 3.5 3.5 3.5 3.5 3.5 3.5 3.5 Water, deionized 45.8 49.3 54.3 59.364.3 69.3 39.3 34.3 29.3 Ethanol USP (200 proof) 43.5 40 35 30 25 20 5055 60 Hydroxypropyl guar 2.4 2.4 2.4 2.4 2.4 2.4 2.4 2.4 2.4hydroxypropyl trimonium chloride² Acetic acid 3.6 3.6 3.6 3.6 3.6 3.63.6 3.6 3.6 Water/Ethanol 1.053 1.233 1.551 1.977 2.572 3.465 0.7860.624 0.488 Acetic acid/Ethanol 0.083 0.090 0.103 0.120 0.144 0.1800.072 0.066 0.060 TOTAL 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0100.0 ¹Schercemol LL ester ²Jaguar C162; CAS No. 71329-50-5; DS 0.10; MS0.6; contains 11/5% w/w water

TABLE 22 Terbinafine HCl Compositions Having Different Water/EthanolWeight Ratios Composition Time R AA AB AC AD AE AF AG AH At 0 hr clearopaque opaque opaque opaque opaque low phase gel gel gel gel gel gel gelviscosity gel separation separation After 1 clear opaque opaque phasephase phase low phase gel week gel gel gel separation separationseparation viscosity gel separation separation

The viscosity of prepared compositions R and AA through AH shown inTable 21, above, was measured using a Brookfield HBDV-I Prime viscometerusing Spindle CPE-51. The viscometer was initialized, calibrated, andzeroed according to manufacturer's recommendations. About 1 gram of thetopical composition was spread uniformly in the sample cup (CPE-44Y) ofthe viscometer and the motor speed was adjusted to 10 revolutions perminute. Viscosity in centipoises (CP) and percent torque were determinedwhen readings stabilized. The results are shown in Table 23, below.

TABLE 23 Viscosity Results Composition R AA AB AC AD AE AF AG AHViscosity (cP) 2361 2030.0 952.8 n/a n/a n/a 1988 456 n/a Torque (%) 5.74.9 2.3 n/a n/a n/a 4.8 1.1 n/a n/a indicates unstable viscosity

Terbinafine hydrochloride compositions containing different amounts ofcationic guar gum were investigated, the appearance thereof noted, andviscosity measured as described hereinabove. The prepared compositions,the noted appearance and measured viscosity are shown in Tables 24, 25and 26, below.

TABLE 24 Terbinafine HCl Compositions With Different Amounts of CationicGuar Gum Composition Ingredient, wt.-% R AI AJ AK AL AM Terbinafine HCl1.2 1.2 1.2 1.2 1.2 1.2 Lauryl lactate¹ 3.5 3.5 3.5 3.5 3.5 3.5 Water,deionized 45.8 46.2 46.7 47.2 45.2 44.7 Ethanol USP (200 proof) 43.543.5 43.5 43.5 43.5 43.5 Hydroxypropyl guar 2.4 2.0 1.5 1.0 3.0 3.5hydroxypropyl trimonium chloride² Acetic acid 3.6 3.6 3.6 3.6 3.6 3.6Water/Ethanol 1.053 1.062 1.074 1.085 1.039 1.028 Acetic acid/Ethanol0.083 0.083 0.083 0.083 0.083 0.083 TOTAL 100.0 100.0 100.0 100.0 100.0100.0 ¹Schercemol LL ester ²Jaguar C162; CAS No. 71329-50-5; DS 0.10; MS0.6; contains 11/5% w/w water

TABLE 25 Terbinafine HCl Compositions Containing Different Amounts ofCationic Guar Gum Composition Time R AI AJ AK AL AM At 0 hr clear clearclear clear clear clear gel gel gel gel gel gel After 1 clear clearclear clear clear clear week gel gel gel gel gel gel

TABLE 26 Viscosity Results Composition R AI AJ AK AL AM Viscos- 23611533.0 704.2 207.1 4929.0 7042.0 ity (cP) Torque 5.7 3.7 1.7 0.5 11.917.0 (%)

Terbinafine hydrochloride compositions containing different amounts ofacetic acid were investigated, the appearance thereof noted, andviscosity measured as described hereinabove. The prepared compositions,the noted appearance and measured viscosity are shown in Tables 27, 28and 29, below.

TABLE 27 Terbinafine HCl Compositions With Different Amounts of AceticAcid Composition Ingredient, wt.-% R AN AO AP AQ AR AS Terbinafine HCl1.2 1.2 1.2 1.2 1.2 1.2 1.2 Lauryl lactate¹ 3.5 3.5 3.5 3.5 3.5 3.5 3.5Water, deionized 45.8 45.8 45.8 45.8 45.8 45.8 45.8 Ethanol USP (200proof) 43.5 46.1 45.1 44.1 43.1 42.1 47.1 Hydroxypropyl guar 2.4 2.4 2.42.4 2.4 2.4 2.4 hydroxypropyl trimonium chloride² Acetic acid 3.6 1 2 34 5 0 Water/Ethanol 1.053 0.994 1.016 1.039 1.063 1.088 0.972 Aceticacid/Ethanol 0.083 0.022 0.044 0.068 0.093 0.119 0 TOTAL 100.0 100.0100.0 100.0 100.0 100.0 100.0 ¹Schercemol LL ester ²Jaguar C162; CAS No.71329-50-5; DS 0.10; MS 0.6; contains 11/5% w/w water

TABLE 28 Terbinafine HCl Compositions Containing Different Amounts ofAcetic Acid Composition Time R AN AO AP AQ AR AS At 0 hr clear veryslightly clear clear clear clear slightly gel opaque gel gel gel gelgel. opaque gel After 1 clear very slightly clear clear clear clearslightly week gel opaque gel gel gel gel gel opaque gel

TABLE 29 Viscosity Results Composition R AN AO AP AQ AR AS Viscosity(cP) 2361 2610 2651 2568 2610 2693 2568 Torque (%) 5.7 6.3 6.4 6.2 6.36.5 6.2

Topical antifungal compositions containing an azole as the antifungalagent are illustrated in Table 30, below.

TABLE 30 Topical Antifungal Azole Compositions Amount, wt.-% IngredientEA EB Efinaconazole 2.0 2.0 Lauryl lactate¹ 2.7 2.7 Water, deionized48.0 48.0 Ethyl alcohol USP (200 proof) 42.6 42.6 Lactic acid 2.7 0Acetic acid 0 2.7 Hydroxypropyl guar hydroxypropyl 2.0 2.0 trimoniumchloride² Water/Ethanol 1.13 1.13 Acid/Ethanol 0.063 0.063 TOTAL 100 100¹Schercemol LL ester ²Jaguar C162; CAS No. 71329-50-5; DS 0.10; MS 0.6;contains 11.5% w/w water

A skin permeation study was performed using the compositions shown inTable 30, above. Cadaver back skin (52-year old male) was used in aFranz cell (3.65 ml volume, 0.55 cm² surface area) with heating/stirringblocks and at a temperature of 35° C. Receptor compartment containedsaline with sodium azide (pH 5.5). Three or four replicates (25 μl and a25 mg control) were prepared. Sampling volume was 300 μL. Fresh bufferwas replaced after each sample removal. Sampling was carried out at 2,4, 6 and 24 hours. The obtained samples were assayed using highperformance liquid chromatography (HPLC). The control was a commerciallyavailable, efinaconazole containing cream (10%), Jublia® cream, DowPharmaceutical Sciences, Inc., Petaluma, CA, having the followingcomposition:

-   -   efinaconazole, 10 wt.-%    -   EDTA disodium, 0.00025 wt.-%    -   water, 1 wt.-%    -   diisopropyl adipate, 12 wt.-%    -   cyclomethicone, 13 wt.-%    -   citric acid, anhydrous, 0.1 wt.-%    -   butylated hydroxytoluene (BHT), 0.1 wt.-%    -   C12-C15 alkyl lactate, 10 wt.-%    -   ethanol, 53.8 wt.-%

The obtained permeation profiles for the compositions of Table 30 arepresented in Table 31, below, and in FIG. 10.

TABLE 31 Permeation Data Cumulative Amount in Receptor, μg/cm² Time,Efinaconazole Jublia ® Hrs. EA ±SD EB ±SD Cream ±SD 2 48.83 38.47 28.735.58 0 0 4 99.35 101.21 69.37 42.61 1.22 2.73 6 152.05 96.06 116.1961.50 3.30 5.08 24 306.53 86.56 219.44 64.04 19.08 22.65

The foregoing data show enhanced permeation of efinaconazole as comparedto a commercially available preparation containing the same activeingredient albeit at a five-fold higher concentration.

The foregoing discussion and the examples are illustrative and are notto be taken as limiting. Still other variants within the spirit andscope of the invention are possible and will readily present themselvesto those skilled in the art.

1. A topical gel composition which comprises an antifungal agentselected from the group consisting of an allylamine and an azole, alactate ester of a C₂ to C₁₆ saturated aliphatic alcohol, an organicacid having a pKa value in the range of about 3.8 to about 5, ethanol,water, and a cationic galactomannan gum.
 2. The composition inaccordance with claim 1 wherein the antifungal agent is an allylamine.3. The composition in accordance with claim 2 wherein the allylamine isa member of the group consisting of terbinafine, naftifine, butenafine,amorolfine and pharmaceutically acceptable salts thereof.
 4. Thecomposition in accordance with claim 2 wherein the allylamine isterbinafine hydrochloride.
 5. The composition in accordance with claim 2wherein the allylamine is amorolfine.
 6. The composition in accordancewith claim 1 wherein the organic acid is acetic acid.
 7. The compositionin accordance with claim 1 wherein the cationic galactomannan gum is acationic polygalactomannan gum ether salt.
 8. The composition inaccordance with claim 7 wherein the cationic polygalactomannan gum ethersalt is hydroxypropyl guar hydroxypropyl trimonium chloride.
 9. Thecomposition in accordance with claim 8 wherein the hydroxypropyl guarhydroxypropyl trimonium chloride has a DS value in the range of about0.07 to about 2 and a MS value in the range of about 0.4 to about 0.8.10. The composition in accordance with claim 8 wherein the hydroxypropylguar hydroxypropyl trimonium chloride has a DS value of about 0.10 and aMS value of about 0.6
 11. The composition in accordance with claim 1comprising, based on the total weight of the composition, about 0.5 toabout 3 percent by weight allylamine, about 1 to about 5 percent byweight lactate ester of a C₂ to C₁₆ saturated aliphatic alcohol, about0.5 to about 5 percent by weight of organic acid, about 35 to about 55percent by weight ethanol, about 35 to about 55 percent by weight water,and about 1 to about 3 percent by weight hydroxypropyl guarhydroxypropyl trimonium chloride.
 12. The composition in accordance withclaim 1 comprising, based on the total weight of the composition, about1.2 percent by weight allylamine, about 3.5 percent by weight lactateester of a C₂ to C₁₆ saturated aliphatic alcohol, about 1 to about 4percent by weight organic acid, about 40 to about 50 percent by weightethanol, about 40 to about 50 percent by weight water, and about 2 toabout 2.5 percent by weight hydroxypropyl guar hydroxypropyl trimoniumchloride.
 13. The composition in accordance with claim 1 containing anallylamine and having a water-to-ethanol weight ratio in the range ofabout 1 to about 1.1 and an acetic acid-to-ethanol weight ratio in therange of about 0.04 to about 0.09.
 14. The composition in accordancewith claim 13 wherein the allylamine is terbinafine hydrochloride. 15.The composition in accordance with claim 13 wherein the allylamine isamorolfine hydrochloride.
 16. The composition in accordance with claim 1wherein the antifungal agent is an azole.
 17. The composition inaccordance with claim 16 wherein the azole is a triazole.
 18. Thecomposition in accordance with claim 17 wherein the triazole isefinaconazole.
 19. The composition in accordance with claim 16comprising, based on the total weight of the composition, about 2percent by weight efinaconazole, about 2.7 percent by weight lauryllactate, about 2.7 percent by weight acetic acid, about 42.6 percent byweight ethanol, about 48 percent by weight water, and about 2 percent byweight hydroxypropyl guar hydroxypropyl trimonium chloride.